ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension.

Germline mutations in genes encoding members of the transforming growth factor-ß (TGF-ß)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curaçao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.

L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition.

Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast.

[Embolization of localized pulmonary arteriovenous malformations in adults]. / Embolisation des malformations artérioveineuses pulmonaires localisées de l'adulte.

OBJECTIVES: To report our experience using embolization in managing localized pulmonary arteriovenous malformations in adults. MATERIAL: and methods. All patients presenting with localized pulmonary arteriovenous malformations treated with embolization were included in the study. Clinical presentation (respiratory symptoms and previous history of paradoxical embolism) and the characteristics of pulmonary arteriovenous malformations (single or multiple, location, diameter of the afferent artery and simple or complex angioarchitecture) before embolization were analyzed. The details of the procedure, including the number of pulmonary arteriovenous malformations embolized, the number of coils used, and the type of intraoperative complications were recorded. Postembolization clinical and imaging follow-up were described. RESULTS: Forty-two patients (26 women, 16 men; mean age, 45 years), including 36 with hereditary hemorrhagic telangiectasia were treated with embolization. Twenty-two patients (53%) were dyspneic and 12 (29%) had a previous history of paradoxical embolism prior to embolization. Forty-seven procedures were carried out on a total of 99 pulmonary arteriovenous malformations (mean, 2.3 per patient), using 530 coils (12.6 per patient). The pulmonary arteriovenous malformations were located in the lower lobes in 60% of cases and a simple architecture was reported in 81% of cases. The average diameter of the afferent artery was 6mm. No preoperative complications were reported. After embolization, two patients (5%) presented with a paradoxical embolism and five patients out of 22 (23%) remained dyspneic. The rate of complete occlusion of treated arteriovenous malformations was 92% using computer tomography. CONCLUSION: Embolization is a highly effective and safe technique for treating pulmonary arteriovenous malformations. Improvement in dyspnea and prevention of paradoxical embolism can be expected. A high technical success rate can be obtained by experienced interventional radiologists.

Serotonin in the regulation of brain microcirculation.

Manipulation of brainstem serotonin (5-HT) raphe neurons induces significant alterations in local cerebral metabolism and perfusion. The vascular consequences of intracerebrally released 5-HT point to a major vasoconstrictor role, resulting in cerebral blood flow (CBF) decreases in several brain regions such as the neocortex. However, vasodilatations, as well as changes in blood-brain barrier (BBB) permeability, which are blocked by 5-HT receptor antagonists also can be observed. A lack of relationship between the changes in flow and metabolism indicates uncoupling between the two variables and is suggestive of a direct neurogenic control by brain intrinsic 5-HT neurons on the microvascular bed. In line with these functional data are the close associations that exist between 5-HT neurons and the microarterioles, capillaries and perivascular astrocytes of various regions but more intimately and/or more frequently so in those where CBF is altered significantly following manipulation of 5-HT neurons. The ability of the microvascular bed to respond directly to intracerebrally released 5-HT is underscored by the expression of distinct 5-HT receptors in the various cellular compartments of the microvascular bed. Thus, it appears that while some 5-HT-mediated microvascular functions involve directly the blood vessel wall, others would be relayed through the perivascular astrocyte. The strategic localization of perivascular astrocytes and the different 5-HT receptors that they harbor strongly emphasize their putative pivotal role in transmitting information between 5-HT neurons and microvessels. It is concluded that the cerebral circulation has full capacity to adequately and locally adapt brain perfusion to changes in central 5-HT neurotransmission either directly or indirectly via the neuronal-astrocytic-vascular tripartite functional unit. Dysfunctions in these neurovascular interactions might result in perfusion deficits and might be involved in specific pathological conditions.

[The role of spiral computerized tomography in the diagnosis of pulmonary embolism]. / Place actuelle de l'angioscanner spiralé dans l'embolie pulmonaire.

The diagnostic strategy of pulmonary embolism has changed in the last few years with the use of the pulmonary spiral angio-scan. It has become the investigation of first intention for the positive diagnosis of pulmonary embolism. Its limitations are known, essentially the difficulties in visualisation of distal pulmonary embolism. However, the introduction of new 64-slice scanners has considerably improved the resolution. The indications of the spiral angioscanner have recently increased with the study of pulmonary artery vascularisation and the calculation of Qanadli's obstruction index, the study of the peripheral venous system and the evaluation of right ventricular dysfunction by the calculation of the ratio of surfaces (or diameters) of RV/LV.

Randomized crossover comparison of DDDR versus VDD pacing after atrioventricular junction ablation for prevention of atrial fibrillation. The atrial pacing peri-ablation for paroxysmal atrial fibrillation (PA (3)) study investigators.

BACKGROUND: Some clinical data suggest that atrial-based pacing prevents paroxysmal atrial fibrillation (AF). This study tested the hypothesis that DDDR pacing compared with VDD pacing prevents AF after atrioventricular (AV) junction ablation. METHODS AND RESULTS: Patients were randomized to DDDR pacing (n=33) or to VDD pacing (n=34) after AV junction ablation and followed every 2 months for 6 months. Patients then crossed over to the alternate pacing mode and were followed for an additional 6 months. Primary analysis included the time to first recurrence of sustained AF (duration >5 minutes), total AF burden, and the development of permanent AF. The time to first episode of AF was similar in the DDDR group (0.37 days, 95% CI 0.1 to 1.3 days) and the VDD pacing group (0.5 days, 95% CI 0.2 to 1.7 days, P=NS). AF burden increased over time in both groups (P<0.01). At the 6-month follow-up, AF burden was 6.93 h/d (95% CI 4. 37 to 10.96 h/d) in the DDDR group and 6.30 h/d (95% CI 3.99 to 9.94 h/d) in the VDD group (P=NS). Twelve (35%) patients in the DDDR group and 11 (32%) patients in the VDD group had permanent AF within 6 months of ablation. Within 1 year of follow-up, 43% of patients had permanent AF. CONCLUSIONS: DDDR pacing compared with VDD pacing does not prevent paroxysmal AF over the long term in patients in the absence of antiarrhythmic drug therapy after total AV junction ablation. Many patients have permanent AF within the first year after ablation.

High energy transcatheter cardioversion of chronic atrial fibrillation.

A new technique of internal transcatheter cardioversion of chronic atrial fibrillation using high energy shocks (200 to 300 joules) was performed in 10 patients. In all patients, external cardioversion (300 to 400 joules) and pharmacologic therapy failed to restore sinus rhythm. Atrial fibrillation was poorly tolerated despite digitalis therapy alone (five patients) or in combination with amiodarone (five patients). High energy transcatheter cardioversion was performed by pulling back the atrioventricular (AV) junction catheter just inferior to the site of His bundle recording and delivering the shock between a proximal electrode (catheter) and backplate (anode). High energy internal cardioversion restored sinus rhythm in 9 of the 10 patients. However, atrial fibrillation recurred within 3 min in two of them; in the remaining patient, the procedure failed to terminate atrial fibrillation. The only complication observed was transient (3 to 315 s) heart block immediately after shock delivery and this was treated by temporary pacing. Seven patients had sinus rhythm on discharge from the hospital, but in three, recurrent atrial fibrillation appeared at 8 days and 2 and 4 months, respectively. A second attempt of transcatheter cardioversion was performed in two patients and was successful in one patient. With a follow-up ranging from 2 to 11 months, five patients continued to have sinus rhythm. These preliminary results suggest that high energy internal cardioversion may be an alternative to AV junction ablation in selected patients with poorly tolerated chronic atrial fibrillation in whom external cardioversion was unsuccessful.

[Erythema nodosum and adenopathy in a 15-year-old boy: uncommon signs of cat scratch disease]. / Erythème noueux et adénopathies chez un adolescent: mode de révélation rare de la maladie des griffes du chat.

UNLABELLED: Erythema nodosum rarely occurs in childhood and can be caused by cat scratch disease, as a result of agent Bartonella henselae. We report the case of a teenager who presented erythema nodosum and bilateral inguinal adenitis. Cat scratch disease diagnosis was confirmed by anti-Bartonella henselae serologies. Despite an appropriate antibiotic therapy, evolution was unfavourable with adenitis abcédation requiring surgical drainage. CONCLUSION: Erythema nodosum in children must let think to cat scratch disease among others etiologies.

Effect of autonomic nervous system modulation on retrograde atrioventricular nodal conduction in the human heart.

Although the influence of the autonomic nervous system on anterograde atrioventricular nodal conduction is well established, its effect on retrograde atrioventricular nodal conduction has not been examined systematically. Since retrograde atrioventricular nodal conduction in subjects with normal anterograde conduction may vary from intact retrograde conduction to complete retrograde block when assessed during ventricular pacing, in this study patients with (a) intact retrograde atrioventricular nodal conduction (group 1) were studied during parasympathetic (vagal) stimulation by carotid sinus pressure and during sympathetic inhibition (propranolol 0.2 mg.kg-1 intravenously) and (b) retrograde atrioventricular nodal block (group 2) were studied during vagal blockade (atropine 0.04 mg.kg-1 intravenously) and during sympathetic stimulation (isoproterenol 1-4 micrograms.min-1 infusion). In both groups changes in sinus cycle length and anterograde atrioventricular nodal conduction were measured. In group 1 vagal stimulation by carotid sinus pressure in 20 patients caused the cycle length at which retrograde atrioventricular nodal block was induced to be significantly lengthened from a mean(SD) of 375(59) to 451(51) ms in six patients; caused complete retrograde block in 10 patients; and had no effect in four patients. Sympathetic inhibition by propranolol in another 15 patients delayed the onset of pacing induced retrograde atrioventricular nodal block from a mean(SD) of 340(60) to 418(80) ms in 11 patients; caused complete retrograde atrioventricular nodal block in three patients; and had no effect in one patient. In group 2 vagal blockade by atropine caused a 1:1 retrograde response during ventricular pacing up to a mean(SD) cycle length of 470(135) ms in six out of eight patients. The infusion of isoproterenol caused the retrograde atrioventricular nodal block to be abolished and 1:1 conduction to be resumed up to a ventricular pacing mean(SD) cycle length of 364(57) ms in six out of eight patients. It is concluded that (a) the autonomic nervous system modulates retrograde atrioventricular nodal conduction in a similar manner to its anterograde counterpart and (b) that since retrograde atrioventricular nodal conduction was reversible after the administration of either atropine or isoproterenol retrograde atrioventricular nodal block may be dynamic (physiological) rather than fixed (anatomical) in nature.

Significance of the cerebrovascular effects of immobilization stress in the rabbit.

The question of the significance of the cerebrovascular effects of stressful situations in animals is still controversial. In the present article, an experimental model of immobilization stress in the rabbit is described, and its specificity in relation to arterial blood pressure and PaCO2 is investigated. CBF was measured with the multiregional tissue sampling technique using [14C]-ethanol as tracer. After dissipation of althesin anesthesia, the stress reaction was elicited by tactile abdominal stimuli. The response was evidenced by an instantaneous acute hypertension (+33.8% during the CBF measurement period). Within the first minute of the reaction, the CBF was significantly increased in all nine structures studied by 39% (caudate nucleus) to 82% (parieto-temporal cortex). The study of the influence of arterial blood pressure and the PaCO2 on CBF showed that cerebrovascular autoregulation and CO2 sensitivity were differently affected in the various structures during the stress reaction. However, the stress response of the brain circulation could not be entirely ascribed to one or both of these two systemic factors, thus suggesting the contribution of a local intrinsic activation. The model presented here could be useful for long-term studies of cerebrovascular repercussions of repeated acute hypertensions of a stressful nature.

Effects of electrical stimulation of the dorsal raphe nucleus on local cerebral blood flow in the rat.

We have studied the effects of electrical stimulation of the dorsal raphe nucleus on local cerebral blood flow (LCBF), as assessed by the quantitative [14C]-iodoantipyrine autoradiographic technique. Stimulation of the dorsal raphe nucleus in the alpha-chloralose anesthetized rat caused a significant decrease in LCBF, ranging from -13 to -26% in 24 brain structures out of 33 investigated. The most pronounced decreases (-23 to -26%) were observed in the accumbens, amygdaloid, interpeduncular nuclei and in the median raphe nucleus, limbic system relays. The decreases also concerned cortical regions and the extrapyramidal system. These results indicate that activation of ascending serotonergic system produces a vasoconstriction and that the dorsal raphe nucleus has a widespread modulatory influence on the cerebral circulation.

Widespread attenuation of the cerebrovascular reactivity to hypercapnia following inhibition of nitric oxide synthase in the conscious rat.

Despite the increasing number of publications devoted to the cerebrovascular role of NO, its precise influence in awake animals is still poorly characterized. The effect of nitric oxide synthase (NOS) inhibition on the cerebrovascular CO2 reactivity was therefore studied in conscious rats. Regional CBF was measured using the [14C]iodoantipyrine technique and brain tissue sampling. The CO2 reactivity was determined 60 min after administration of 30 mg kg-1 N omega-nitro-L-arginine methyl ester (L-NAME). Blockade of NOS by L-NAME significantly decreased CBF in all 11 brain regions studied (-17 to -49%) and increased arterial pressure from 117 +/- 12 to 147 +/- 11 mn Hg. In control conditions, CO2 responsiveness ranged from 1.3 +/- 0.4 in the hypophysis to 6.4 +/- 0.6 ml 100 g-1 min-1 mm Hg-1 in the parietal cortex. Following L-NAME injection, the reactivity to hypercapnia was significantly attenuated in all structures, the magnitude of the reduction ranging from 57% in the medulla to 74% in the cerebellum. This result shows that NO is an important mediator of the hypercapnic vasodilation in the conscious rat.

Local uncoupling of the cerebrovascular and metabolic responses to somatosensory stimulation after neuronal nitric oxide synthase inhibition.

It has recently been shown, using either genetically engineered mutant mice (nitric oxide synthase [NOS] knockout) or specific pharmacological tools, that type I NOS (neuronal isoform of NOS, [nNOS]) participates in coupling cerebral blood flow to functional activation. However, it has not been clearly established whether the associated metabolic response was preserved under nNOS inhibition and whether this action was exerted homogeneously within the brain. To address these issues, we analyzed the combined circulatory and metabolic consequences of inhibiting the nNOS both at rest and during functional activation in the rat anesthetized with alpha-chloralose. Cerebral blood flow and cerebral glucose use (CGU) were measured autoradiographically using [14C]iodoantipyrine and [14C]2-deoxyglucose during trigeminal activation induced by unilateral whiskers stimulation in vehicle- and 7-nitroindazole-treated rats. Our data show that inhibition of nNOS globally decreased CBF without altering CGU, indicating that NO-releasing neurons play a significant role in maintaining a resting cerebrovascular tone in the whole brain. During whisker stimulation, nNOS inhibition totally abolished the cerebrovascular response only in the second order relay stations (thalamus and somatosensory cortex) of the trigeminal relay without altering the metabolic response. These findings provide evidence that the involvement of neurally-derived NO in coupling flow to somatosensory activation is region-dependent, and that under nNOS inhibition, CBF and CGU may vary independently during neuronal activation.

Cerebral blood flow and blood-brain influx of some neutral amino acids in control and hypothyroid 16-day-old rats.

Rats were made hypothyroid by a daily subcutaneous injection of propylthiouracil beginning the first day after birth. CBF, brain plasma volume, blood-brain extraction, and influx of some neutral amino acids were studied in 16-day-old animals. In hypothyroid rats, the brain plasma volume was decreased by approximately 30%. CBF was decreased by greater than 50%. This decrease was the highest in cerebellum. Blood-brain extraction of small neutral amino acids (alanine, serine, cysteine) was greatly enhanced. This greater extraction compensated for the decreased supply of alanine brought about by its decreased plasma concentration and the lower CBF. In contrast, the extraction of the large amino acids tested (leucine, phenylalanine) was hardly increased, and the influx of phenylalanine was slightly decreased. These results suggest an alteration in the maturation of the brain capillary bed and capillary transport for neutral amino acids in hypothyroidism. The differential effect of hypothyroidism on some small and large amino acids is an additional argument for the existence of two systems of transport for neutral amino acids at the luminal membrane of brain capillary endothelial cells of immature rats.

Autoradiographic evidence for flow-metabolism uncoupling during stimulation of the nucleus basalis of Meynert in the conscious rat.

We earlier reported that electrical stimulation of the rat nucleus basalis of Meynert (NBM) induces large cerebral blood flow increases, particularly in frontal cortical areas but also in some subcortical regions. The present study was designed to address the issue of blood flow control exerted by NBM projections. To this aim, we have determined whether these flow increases were associated with proportionate changes in metabolic activity as evaluated by cerebral glucose utilization (CGU) strictly under the same experimental conditions in the conscious rat. An electrode was chronically implanted in a reactive site of the NBM as determined by laser-Doppler flowmetry (LDF) of the cortical circulation. One to two weeks later, while the cortical blood flow was monitored by LDF, we measured CGU using the [14C]2-deoxyglucose autoradiographic technique during unilateral electrical stimulation of the NBM, and analyzed the local flow-metabolism relationship. The large increases in cortical blood flow induced by NBM stimulation, exceeding 300% in various frontal areas, were associated with at most 24% increases in CGU (as compared with the control group) in one frontal area. By contrast, strong increases in CGU exceeding 150% were observed in subcortical regions ipsilateral to the stimulation, especially in extrapyramidal structures, associated with proportionate CBF changes. Thus, none of the blood flow changes observed in the cortex can be ascribed to an increased metabolic activity, whereas CBF and CGU were coupled in many subcortical areas. This result indicates that different mechanisms, which do not necessarily involve any metabolic factor, contribute to the regulation of the cerebral circulation at the cortical and subcortical level. Because the distribution of the uncoupling is coincident with that of cholinergic NBM projections directly reaching cortical microvessels, these data strongly support the hypothesis that NBM neurons are capable of exerting a neurogenic control of the cortical microcirculation.

Differential effects of electrical stimulation of the dorsal raphe nucleus and of cervical sympathectomy on serotonin and noradrenaline concentrations in major cerebral arteries and pial vessels in the rat.

The levels of noradrenaline (NA), serotonin (5-HT), and 5-hydroxyindoleacetic acid were measured by HPLC and compared between the large arteries of the circle of Willis and the small pial vessels in the rat, following either electrical stimulation of the dorsal raphe nucleus or bilateral superior cervical ganglionectomy. With electrical stimulation, the 5-HT concentrations were reduced (-48%) in the small pial vessels, but were unchanged in the major cerebral arteries. NA concentrations were dramatically reduced following cervical sympathectomy in the large arteries (-77%), though the reduction was less pronounced (-34%) in the small vessels. Sympathectomy caused a significant decrease in the 5-HT concentration of the major cerebral arteries (-33%), but was without effect on the 5-HT levels of the small pial vessels. These results show that an appreciable fraction of the perivascular 5-HT measured in the small pial and the large cerebral arteries originates from different sources.

Local injection of antisense oligonucleotides targeted to the glial glutamate transporter GLAST decreases the metabolic response to somatosensory activation.

The mechanisms responsible for the local increase in brain glucose utilization during functional activation remain unknown. Recent in vitro studies have identified a new signaling pathway involving an activation of glial glutamate transporters and enhancement of neuron-astrocyte metabolic interactions that suggest a putative coupling mechanism. The aim of the present study was to determine whether one of the glutamate transporters exclusively expressed in astrocytes, GLAST, is involved in the neurometabolic coupling in vivo. For this purpose, rats were microinjected into the posteromedial barrel subfield (PMBSF) of the somatosensory cortex with GLAST antisense or random phosphorothioate oligonucleotides. The physiologic activation was performed by stimulating the whisker-to-barrel pathway in anesthetized rats while measuring local cerebral glucose utilization by quantitative autoradiography in the PMBSF. Twenty-four hours after injection of two different antisense GLAST oligonucleotide sequences, and despite the presence of normal whisker-related neuronal activity in the PMBSF, the metabolic response to whisker stimulation was decreased by more than 50%. Injection of the corresponding random sequences still allowed a significant increase in glucose utilization in the activated area. The present study highlights the contribution of astrocytes to neurometabolic coupling in vivo. It provides evidence that glial glutamate transporters are key molecular components of this coupling and that neuronal glutamatergic activity is an important determinant of energy utilization. Results indicate that astrocytes should also be considered as possible sources of altered brain metabolism that could explain the distinct imaging signals observed in some pathologic situations.

Lymphocyte glutathione status in relation to their Con A proliferative response.

We studied the intracellular total, oxidized and reduced glutathione levels in thymus and spleen rat lymphocytes cultured with or without Con A and 2-mercaptoethanol (2-ME). After 48 h culture, the total glutathione level decreased and the oxidized glutathione level increased in the two types of unstimulated and stimulated cells. In the presence of 2-ME, the tritiated thymidine incorporation increased in splenocytes but not in thymocytes; on the other hand, the two types of stimulated cells increased their total and oxidized glutathione content. The enhancement of the GSSG/GSH + GSSG ratio, irrespective of culture conditions, indicates a severely disturbed redox state of the cells. 2-ME acts on the glutathione synthesis of stimulated lymphocytes but is unable to maintain a normal redox state of these cells.

Prealbumin-retinol-binding-protein-retinol complex in hemodialysis patients.

In hemodialysis (HD) patients, serum prealbumin (TBPA) is correlated to nutritional status and outcome despite usually elevated serum levels. The purpose of this work was to study the role of TBPA-retinol-binding-protein (RBP)-retinol complex changes in the elevation of serum TBPA in HD patients. Serum TBPA, RBP, and retinol were measured in 30 otherwise healthy HD patients (15 men, 15 women) and in 30 healthy volunteers (15 men, 15 women). The dependence of TBPA on RBP was studied by covariance and regression methods. TBPA (p less than 0.05), RBP (p less than 0.01), and retinol (p less than 0.05) were elevated in HD patients. Elevated TBPA was associated with a decrease of TBPA free from RBP (p less than 0.01). The decrease of free TBPA may explain the reduction of TBPA breakdown and its elevation in HD patients.